During aging, the neuronal response to endogenous and exogenous environmental stress undergoes continuous modulation. The accumulation of protein fragments, such as amyloid beta-peptide (A[unreadable]), within brain parenchyma and vasculature provides a modified context in which homeostatic and reparative processes are operative. The central theme of our Program Project is that specific, cell associated cofactors, RAGE (Receptor for AGEs) and ABAD (A[unreadable] ?binding alcohol dehydrogenase) are critical for concentrating the effects of low levels of A[unreadable], relevant to early stages of pathogenicity in Alzheimer's disease (AD) on vulnerable cells, hi the past grant period, we and others have provided experimental evidence to support a link between RAGE or ABAD and A[unreadable]-mediated cell stress. These same cofactors may play a pivotal role in innate, neuroprotective pathways that orchestrate reparative processes through a complex integration of host response mechanisms. The goal of this competitive renewal of this PROGRAM PROJECT is to further elucidate the mechanisms of RAGE/ABAD-mediated cell stress &rescue relevant to Aging and the Nervous System. Project 1 will analyze the contribution of RAGE signaling to neuronal and microglial stress in an A[unreadable]-rich milieu and will determine the effect of RAGE blockade on neuronal stress by cross-breeding homozygous RAGE null mice with transgenic (Tg) mice overexpressing mutant [unreadable]APP (Tg mAPP), and by a decoy receptor, soluble RAGE. Project 2 will examine the impact of RAGE in neuronal repair mechanisms in the peripheral nervous system affected by chronic accumulation of RAGE ligands, Advanced Glycation Endproducts, in diabetes. Projects 3-4 will analyze critical aspects of the intracellular pathway through which ABAD engages AB, cyclophilin D (cypD), and ABAD-A[unreadable] ?complex induces neuronal and mitochondria! stress, synaptic dysfunction and impaired memory in an A[unreadable]-rich environment using Tg (#3) and in vitro models (#3 &4), as well as structural studies to probe ABAD-A[unreadable], ABAD-cyclophilin D complex (#4). Analysis of overlapping cellular effector mechanisms triggered by activation of RAGE and ABAD requires shared molecular tools and animal models, and provides the basis for synergy among the four projects. At the end of this PROGRAM PROJECT, we expect to have generated new and important information related to the involvement of RAGE and ABAD in neuronal perturbation and repair as a key step in evaluating their efficacy as future therapeutic targets in neurodegenerative disorders.